Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases
Authors: Brian Kim, Marc E. Rothenberg, Xin Sun, Claus Bachert, David Artis, Raza Zaheer, Yamo Deniz, Paul Rowe, Sonya Cyr
Journal: Journal of Allergy and Clinical Immunology (2023)

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation. Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation. Type 2 immunity is a specialized, evolutionarily conserved arm of the immune system that combats ectoparasitic and endoparasitic helminths, expels toxins, and promotes tissue repair.1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar, 2Gandhi N.A. Pirozzi G. Graham N.M. Commonality of the IL-4/IL-13 pathway in atopic diseases.Expert Rev Clin Immunol. 2017; 13: 425-437Crossref PubMed Scopus (276) Google Scholar, 3Kopp E.B. Agaronyan K. Licona-Limon I. Nish S.A. Medzhitov R. Modes of type 2 immune response initiation.Immunity. 2023; 56: 667-694Abstract Full Text Full Text PDF Scopus (1) Google Scholar, 4Molofsky A.B. Locksley R.M. The ins and outs of innate and adaptive type 2 immunity.Immunity. 2023; 56: 704-722Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar When the epithelial barrier is breached, alarmin cytokines (eg, thymic stromal lymphopoietin [TSLP], IL-25, IL-33) activate tissue-resident immune cells (such as mast cells, dendritic cells, and group 2 innate lymphoid cells [ILC2s]) while simultaneously recruiting granulocytes, including eosinophils and basophils. Collectively, these cells orchestrate a polarized type 2 immune response through type 2 cytokines, histamine, and other mediators that neutralize and expel parasitic helminths and toxins and repair the barrier through epithelial turnover, remodeling, and fibrosis. Although these processes are protective and intended to restore tissue homeostasis, in the setting of allergy and continuous barrier stress they become pathologic, resulting in a variety of chronic inflammatory diseases. Mechanical reflexes such as scratching, airway constriction, coughing, sneezing, and gastrointestinal motility also protect barrier surfaces and are triggered by direct activation of sensory neurons, often in concert with autonomic input to the target organs. Many of these manifestations are pathologically altered in diseases with type 2 immune dysregulation (Fig 1), including (but not limited to) atopic dermatitis (AD), prurigo nodularis (PN), asthma, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic esophagitis (EoE).1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers of type 2 inflammation in disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar,2Gandhi N.A. Pirozzi G. Graham N.M. Commonality of the IL-4/IL-13 pathway in atopic diseases.Expert Rev Clin Immunol. 2017; 13: 425-437Crossref PubMed Scopus (276) Google Scholar,5Hamilton J.D. Harel S. Swanson B.N. Brian W. Chen Z. Rice M.S. et al.Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.Clin Exp Allergy. 2021; 51: 915-931Crossref PubMed Scopus (59) Google Scholar,6Le Floc'h A. Allinne J. Nagashima K. Scott G. Birchard D. Asrat S. et al.Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation.Allergy. 2020; 75: 1188-1204Crossref PubMed Scopus (163) Google Scholar The extent of similarities among the neuroimmune pathways regulating these mechanical responses remains to be fully defined (Table I7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides activate human mast cell degranulation and chemokine production.Immunology. 2008; 123: 398-410Crossref PubMed Scopus (340) Google Scholar, 8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho M. Johansson O. Histamine-containing mast cells and their relationship to NGFr-immunoreactive nerves in prurigo nodularis: a reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref PubMed Scopus (49) Google Scholar, 9Sonkoly E. Muller A. Lauerma A.I. Pivarcsi A. Soto H. Kemeny L. et al.IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol. 2006; 117: 411-417Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar, 10Tominaga M. Takamori K. Peripheral itch sensitization in atopic dermatitis.Allergol Int. 2022; 71: 265-277Crossref Scopus (19) Google Scholar, 11Garcovich S. Maurelli M. Gisondi P. Peris K. Yosipovitch G. Girolomoni G. Pruritus as a distinctive feature of type 2 inflammation.Vaccines (Basel). 2021; 9: 303Crossref PubMed Scopus (50) Google Scholar, 12Kim Y.J. Granstein R.D. Roles of calcitonin gene-related peptide in the skin, and other physiological and pathophysiological functions.Brain Behav Immun Health. 2021; 18100361PubMed Google Scholar, 13Wang F. Trier A.M. Li F. Kim S. Chen Z. Chai J.N. et al.A basophil-neuronal axis promotes itch.Cell. 2021; 184: 422-440.e17Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 14Liu B. Tai Y. Achanta S. Kaelberer M.M. Caceres A.I. Shao X. et al.IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.Proc Natl Acad Sci U S A. 2016; 113: E7572-E7579Crossref PubMed Scopus (179) Google Scholar, 15Wilson S.R. Thé L. Batia L.M. Beattie K. Katibah G.E. McClain S.P. et al.The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell. 2013; 155: 285-295Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar, 16Trier A.M. Mack M.R. Fredman A. Tamari M. Ver Heul A.M. Zhao Y. et al.IL-33 signaling in sensory neurons promoted dry skin itch.J Allergy Clin Immunol. 2022; 149: 1473-1480Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Simpson E.L. Parnes J.R. She D. Crouch S. Rees W. Mo M. et al.Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial.J Am Acad Dermatol. 2019; 80: 1013-1021Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Oetjen L.K. Mack M.R. Feng J. Whelan T.M. Niu H. Guo C.J. et al.Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.Cell. 2017; 171: 217-228.e13Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar, 19Cevikbas F. Wang X. Akiyama A. Kempkes C. Savinko T. Antal A. et al.A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1.J Allergy Clin Immunol. 2014; 133: 448-460Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar, 20Blauvelt A. de Bruin-Weller M. Gooderham M. Cather J.C. Weisman J. Pariser D. et al.Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomized, double-blinded, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 2287-2303Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar, 21Silverberg J.I. Simpson E.L. Ardeleanu M. Thaçi D. Barbarot S. Bagel J. et al.Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the Investigator's Global Assessment: a pooled analysis of data from two phase III trials.Br J Dermatol. 2019; 181: 80-87Crossref PubMed Scopus (39) Google Scholar, 22Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (1254) Google Scholar, 23Thaçi D. Simpson E.L. Deleuran M. Kataoka Y. Chen Z. Gadkari A. et al.Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2).J Dermatol Sci. 2019; 94: 266-275Abstract Full Text Full Text PDF PubMed Google Scholar, 24Simpson E.L. Paller A.S. Siegfried E.C. Boguniewicz M. Sher L. Gooderham M.J. et al.Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial.JAMA Dermatol. 2020; 156: 44-56Crossref PubMed Scopus (254) Google Scholar, 25Paller A.S. Siegfried E.C. Thaçi D. Wollenberg A. Cork M.J. Arkwright P.D. et al.Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: a randomized, double-blinded, placebo-controlled phase 3 trial.J Am Acad Dermatol. 2020; 83: 1282-1293Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 26Paller A.S. Simpson E.L. Siegfried E.C. Cork M.J. Wollenberg A. Arkwright P.D. et al.Dupilumab in children ages 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled phase 3 trial.Lancet. 2022; 400: 908-919Abstract Full Text Full Text PDF PubMed Google Scholar, 27Wollenberg A. Blauvelt A. Guttman-Yassky E. Worm M. Lynde C. Lacour J.P. et al.Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).Br J Dermatol. 2021; 184: 437-449Crossref PubMed Scopus (214) Google Scholar, 28Wollenberg A. Howell M.D. Guttman-Yassky E. Silverberg J.I. Kell C. Ranade K. et al.Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.J. Allergy Clin. Immunol. 2019; 143: 135-141Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 29Gutermuth J. Pink A.E. Worm M. Soldbro L. Bjerregård Øland C. Weidinger S. Tralokinumab plus topical corticosteroids in adults with severe atopic dermatitis and inadequate response to or intolerance of ciclosporin A: a placebo-controlled, randomized, phase III clinical trial (ECZTRA 7).Br J Dermatol. 2022; 186: 440-452Crossref PubMed Scopus (26) Google Scholar, 30Silverberg J.I. Toth D. Bieber T. Alexis A.F. Elewski B.E. Pink A.E. et al.Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.Br J Dermatol. 2021; 184: 450-463Crossref PubMed Scopus (133) Google Scholar, 31Simpson E.L. Carsten Flohr C. Eichenfield L.F. Bieber T. Sofen H. Taïeb A. et al.Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE).J Am Acad Dermatol. 2018; 78: 863-871.e11Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 32Guttman-Yassky E. Blauvelt A. Eichenfield L.F. Paller A.S. Armstrong A.W. Drew J. et al.Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis. A phase 2b randomized clinical trial.JAMA Dermatol. 2020; 156: 411-420Crossref PubMed Scopus (0) Google Scholar, 33Silverberg J.I. Guttman-Yassky E. Thaçi D. Irvine A.D. Stein Gold L. Blauvelt A. et al.Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis.N Engl J Med. 2023; 388: 1080-1091Crossref PubMed Scopus (16) Google Scholar, 34Silverberg J.I. Pinter A. Pulka G. Poulin Y. Bouaziz J.D. Wollenberg A. et al.Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus.J Allergy Clin Immunol. 2020; 145: 173-182Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 35Kabashima K. Matsumura T. Komazaki H. Kawashima M. Nemolizumab JP01 and JP02 Study Group. Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate-to-severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: results from two phase III, long-term studies.Br J Dermatol. 2022; 186: 642-651Crossref PubMed Scopus (0) Google Scholar, 36Ständer S. Yosipovitch G. Legat F.J. Lacour J.P. Paul C. Narbutt J. et al.Trial of nemolizumab in moderate-to-severe prurigo nodularis.N Engl J Med. 2020; 382: 706-716Crossref PubMed Scopus (144) Google Scholar, 37Kamata M. Tada Y. Optimal use of Jak inhibitors and biologics for atopic dermatitis on the basis of the current evidence.JID Innov. 2023; 3100195Abstract Full Text Full Text PDF Google Scholar, 38Bieber T. Paller A.S. Kabashima K. et al.Atopic dermatitis: pathomechanisms and lessons learned from novel systemic therapeutic options.JEADV. 2022; 36: 1432-1449Google Scholar, 39Lee K.P. Plante J. Korte J.E. Elston D.M. Oral Janus kinase inhibitors in the treatment of atopic dermatitis: A systematic review and meta-analysis.Skin Health Dis. 2023; 3: e133Crossref PubMed Scopus (0) Google Scholar, 40Rodriguez-Roy Y. Ficheux A.-S. Misery L. Brenaut Efficacy of topical and systemic treatments for atopic dermatitis on pruritus: A systematic literature review and meta-analysis.Front Med. 2022; 91079323Google Scholar, 41Huang I.-H. Chung W.-H. Wu P.-C. Chen C.-B. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review.Front Immunol. 2022; 131068260Crossref Scopus (12) Google Scholar, 42Haas S. Capellino S. Phan N.Q. Böhm M. Luger T.A. Straub R.H. et al.Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis.J Dermatol Sci. 2010; 58: 193-197Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 43Liang Y. Jacobi H.H. Reimert C.M. Haak-Frendscho M. Marcusson J.A. Johansson O. CGRP-immunoreactive nerves in prurigo nodularis—an exploration of neurogenic inflammation.J Cutan Pathol. 2000; 27: 359-366Crossref PubMed Scopus (62) Google Scholar, 44Williams K.A. Huang A.H. Belzberg M. Kwatra S.G. Prurigo nodularis: pathogenesis and management.J Am Acad Dermatol. 2020; 83: 1567-1575Abstract Full Text Full Text PDF PubMed Google Scholar, 45Molina F.A. Burrows N.P. Jones R.R. Terenghi G. Polak J.M. Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis.Br J Dermatol. 1992; 127: 344-351Crossref PubMed Scopus (0) Google Scholar, 46Kabata H. Artis D. Neuro-immune crosstalk and allergic inflammation.J Clin Invest. 2019; 129: 1475-1482Crossref PubMed Scopus (88) Google Scholar, 47Teresiak-Mikołajczak E. Czarnecka-Operacz M. Jenerowicz D. Silny W. Neurogenic markers of the inflammatory process in atopic dermatitis: relation to the severity and pruritus.Postepy Dermatol Alergol. 2013; 30: 286-292Crossref PubMed Scopus (33) Google Scholar, 48Yang T.B. Kim B.S. Clinical Review: Pruritus in allergy and immunology.J Allergy Clin Immunol. 2019; 144: 353-360Abstract Full Text Full Text PDF PubMed Google Scholar, 49Hashimoto T. Nattkemper L.A. Kim H.S. et al.Itch intensity in prurigo nodularis is closely related to dermal interleukin-31, oncostatin M, IL-31 receptor alpha and oncostatin M receptor beta.Exp Dermatol. 2021; 30: 804-810Crossref PubMed Scopus (44) Google Scholar, 50Stott B. Lavender P. Lehmann S. Pennino D. Durham S. Schmidt-Weber C.B. Human IL-31 is induced by IL-4 and promotes Th2-driven inflammation.J Allergy Clin Immunol. 2013; 132: 446-454Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 51Macdonald L.E. Karow M. Stevens S. Auerbach W. Poueymirou W.T. Jason Yasenchak J. et al.Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes.Proc Natl Acad Sci U S A. 2014; 111: 5147-5152Crossref PubMed Scopus (237) Google Scholar, 52Ständer S. Yosipovitch G. Lacour J.P. Legat F.J. Paul C. Reich A. et al.Nemolizumab efficacy in prurigo nodularis: onset of action on itch and sleep disturbances.J Eur Acad Dermatol Venereol. 2022; 36: 1820-1825Crossref PubMed Scopus (0) Google Scholar, 53Fryer A.D. Stein L.H. Nie Z. Curtis D.E. Evans C.M. Hodgson S.T. et al.Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction.J Clin Invest. 2006; 116: 228-236Crossref PubMed Scopus (122) Google Scholar, 54Grunig G. Warnock M. Wakil A.E. Venkayya R. Brombacher F. Rennick D.M. et al.Requirement for IL-13 independently of IL-4 in experimental asthma.Science. 1998; 282: 2261-2263Crossref PubMed Scopus (1748) Google Scholar, 55Wills-Karp J. Luyimbazi K.J. Xu X. Schofield B. Neben T.Y. Karp C.L. et al.Interleukin-13: central mediator of allergic asthma.Science. 1998; 282: 2258-2261Crossref PubMed Scopus (2410) Google Scholar, 56Manson M.L. Jesper Säfholm J. James A. Johnsson A. Bergman P. Al-Ameri M. et al.IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways.J Allergy Clin Immunol. 2020; 145: 808-817Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 57Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast-cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (1079) Google Scholar, 58Weigand L.A. Myers A.C. Meeker S. Undem B.J. Mast cell-cholinergic nerve interaction in mouse airways.J Physiol. 2009; 587: 3355-3362Crossref PubMed Scopus (55) Google Scholar, 59Klose C.S.N. Mahlakõiv T. Moeller J.B. Rankin L.C. Flamar A.L. Kabata H. et al.The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.Nature. 2017; 549: 282-286Crossref PubMed Scopus (350) Google Scholar, 60Cardoso V. Chesné J. Ribeiro H. García-Cassani B. Carvalho T. Bouchery T. et al.Neuronal regulation of type 2 innate lymphoid cells via neuromedin U.Nature. 2017; 549: 277-281Crossref PubMed Scopus (368) Google Scholar, 61Perner C. Flayer C.H. Zhu X. Aderhold P.A. Dewan Z.N.A. Voisin T. et al.Substance P release by sensory neurons triggers dendritic cell migration and initiates the type-2 immune response to allergens.Immunity. 2020; 53: 1063-1077Abstract Full Text Full Text PDF PubMed Google Scholar, 62Moriyama S. Brestoff J.R. Flamar A.L. Moeller J.B. Klose C.S.N. Rankin L.C. et al.β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses.Science. 2018; 359: 1056-1061Crossref PubMed Scopus (236) Google Scholar, 63Sui P. Wiesner D.L. Xu J. Zhang Y. Lee J. Van Dyken S. et al.Pulmonary neuroendocrine cells amplify allergic asthma responses.Science. 2018; 360eaan8546Crossref PubMed Scopus (228) Google Scholar, 64Hara Y. Jha M.K. Mattoo H. Nash S. Khan A. Orengo J. et al.Interleukin 4 directly activates olfactory neurons and induces loss of smell in mice.J Allergy Clin Immunol. 2023; 151: AB128Abstract Full Text Full Text PDF Google Scholar, 65Rouyar A. Classe M. Gorski R. Bock M.D. Le-Guern J. Roche S. et al.Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model.Allergy. 2019; 74: 549-559Crossref PubMed Scopus (14) Google Scholar, 66Backaert W. Steelant B. Hellings P.W. Talavera K. Van Gerven L. A TRiP through the roles of transient receptor potential cation channels in type 2 upper airway inflammation.Curr Allergy Asthma Rep. 2021; 21: 20Crossref PubMed Scopus (0) Google Scholar, 67Li F. Jiang H. Shen X. et al.Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem.Cell. 2021; 184: 3762-3773Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 68Samivel R. Kim D.W. Son H.R. et al.The role of TRPV1 in the CD4+ T cell-mediated inflammatory response of allergic rhinitis.Oncotarget. 2015; 7: 148-160Crossref Google Scholar, 69Yu M. Chang C. Undem B.J. Yu S. Capsaicin-sensitive vagal afferent nerve-mediated interoceptive signals in the esophagus.Molecules. 2021; 26: 3929Crossref Scopus (3) Google Scholar, 70O'Shea K.M. Aceves S.S. Dellon E.S. Pathophysiology of eosinophilic esophagitis.Gastroenterology. 2018; 154: 333-345Abstract Full Text Full Text PDF PubMed Google Scholar, 71Akiho H. Ihara E. Motomura Y. Nakamura K. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders.World J Gastrointest Pathophysiol. 2011; 2: 72-81Crossref PubMed Google Scholar, 72Hu Y. Liu Z. Yu X. et al.Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis.Am J Physiol Gastrointest Liver Physiol. 2014; 307: G149-G157Crossref Scopus (21) Google Scholar, 73Zhang S. Shoda T. Aceves S.S. Arva N.C. Chehade M. Collins M.H. et al.Mast cell-pain connection in eosinophilic esophagitis.Allergy. 2022; 77: 1895-1899Crossref PubMed Scopus (8) Google Scholar).Table INeuroimmune interactions affecting symptoms in AD, PN, asthma, CRSwNP, and EoEConditionSymptomsNeuroimmune interactionsType 2 cytokine profileADPruritus•Colocalization of neurons and immune cells7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides activate human mast cell degranulation and chemokine production.Immunology. 2008; 123: 398-410Crossref PubMed Scopus (340) Google Scholar,8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho M. Johansson O. Histamine-containing mast cells and their relationship to NGFr-immunoreactive nerves in prurigo nodularis: a reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref PubMed Scopus (49) Google Scholar•Type 2 cytokines and OSM promote pruritogen sensitization9Sonkoly E. Muller A. Lauerma A.I. Pivarcsi A. Soto H. Kemeny L. et al.IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol. 2006; 117: 411-417Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar•Neuropeptide release from sensory neurons induces proinflammatory cytokines and activates immune cells (eg, mast cells, basophils)7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides activate human mast cell degranulation and chemokine production.Immunology. 2008; 123: 398-410Crossref PubMed Scopus (340) Google Scholar,8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho M. Johansson O. Histamine-containing mast cells and their relationship to NGFr-immunoreactive nerves in prurigo nodularis: a reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref PubMed Scopus (49) Google Scholar,10Tominaga M. Takamori K. Peripheral itch sensitization in atopic dermatitis.Allergol Int. 2022; 71: 265-277Crossref Scopus (19) Google Scholar, 11Garcovich S. Maurelli M. Gisondi P. Peris K. Yosipovitch G. Girolomoni G. Pruritus as a distinctive feature of type 2 inflammation.Vaccines (Basel). 2021; 9: 303Crossref PubMed Scopus (50) Google Scholar, 12Kim Y.J. Granstein R.D. Roles of calcitonin gene-related peptide in the skin, and other physiological and pathophysiological functions.Brain Behav Immun Health. 2021; 18100361PubMed Google Scholar, 13Wang F. Trier A.M. Li F. Kim S. Chen Z. Chai J.N. et al.A basophil-neuronal axis promotes itch.Cell. 2021; 184: 422-440.e17Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar•Scratching causes release of alarmins (eg, IL-33), which can act directly on sensory neurons9Sonkoly E. Muller A. Lauerma A.I. Pivarcsi A. Soto H. Kemeny L. et al.IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol. 2006; 117: 411-417Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar,11Garcovich S. Maurelli M. Gisondi P. Peris K. Yosipovitch G. Girolomoni G. Pruritus as a distinctive feature of type 2 inflammation.Vaccines (Basel). 2021; 9: 303Crossref PubMed Scopus (50) Google Scholar,14Liu B. Tai Y. Achanta S. Kaelberer M.M. Caceres A.I. Shao X. et al.IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.Proc Natl Acad Sci U S A. 2016; 113: E7572-E7579Crossref PubMed Scopus (179) Google Scholar, 15Wilson S.R. Thé L. Batia L.M. Beattie K. Katibah G.E. McClain S.P. et al.The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell. 2013; 155: 285-295Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar, 16Trier A.M. Mack M.R. Fredman A. Tamari M. Ver Heul A.M. Zhao Y. et al.IL-33 signaling in sensory neurons promoted dry skin itch.J Allergy Clin Immunol. 2022; 149: 1473-1480Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 17Simpson E.L. Parnes J.R. She D. Crouch S. Rees W. Mo M. et al.Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial.J Am Acad Dermatol. 2019; 80: 1013-1021Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar•Some sensory neurons express receptors for IL-4, IL-13, IL-31, TRPA1, TRPV118Oetjen L.K. Mack M.R. Feng J. Whelan T.M. Niu H. Guo C.J. et al.Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.Cell. 2017; 171: 217-228.e13Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar,19Cevikbas F. Wang X. Akiyama A. Kempkes C. Savinko T. Antal A. et al.A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1.J Allergy Clin Immunol. 2014; 133: 448-460Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar•Reducing type 2 inflammation reduces itch20Blauvelt A. de Bruin-Weller M. Gooderham M. Cather J.C. Weisman J. Pariser D. et al.Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomized, double-blinded, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 2287-2303Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar, 21Silverberg J.I. Simpson E.L. Ardeleanu M. Thaçi D. Barbarot S. Bagel J. et al.Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the Investigator's Global Assessment: a pooled analysis of data from two phase III trials.Br J Dermatol. 2019; 181: 80-87Crossref PubMed Scopus (39) Google Scholar, 22Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (1254) Google Scholar, 23Thaçi D. Simpson E.L. Deleuran M. Kataoka Y. Chen Z. Gadkari A. et al.Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2).J Dermatol Sci. 2019; 94: 266-275Abstract Full Text Full Text PDF PubMed Google Scholar, 24Simpson E.L. Paller A.S. Siegfried E.C. Boguniewicz M. Sher L. Gooderham M.J. et al.Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial.JAMA Dermatol. 2020; 156: 44-56Crossref PubMed Scopus (254) Google Scholar, 25Paller A.S. Siegfried E.C. Thaçi D. Wollenberg A. Cork M.J. Arkwright P.D. et al.Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: a randomized, double-blinded, placebo-controlled phase 3 trial.J Am Acad Dermatol. 2020; 83: 1282-1293Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 26Paller A.S. Simpson E.L. Siegfried E.C. Cork M.J. Wollenberg A. Arkwright P.D. et al.Dupilumab in children ages 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled phase 3 trial.Lancet. 2022; 400: 908-919Abstract Full Text Full Text PDF PubMed Google Scholar, 27Wollenberg A. Blauvelt A. Guttman-Yassky E. Worm M. Lynde C. Lacour J.P. et al.Tralokinumab for moderate-to-severe atopic dermatitis: results from